Topically Active Steroids for Use in Interstitial Pulmonary Fibrosis

ABSTRACT

The present invention features methods of delivering corticosteroids or metabolites thereof for treating inflammatory conditions otherwise difficult to cure with topical administration.

RELATED APPLICATIONS

This application is a United States National Stage Application claimingpriority under 35 U.S.C. 371 from International Patent Application No.PCT/US09/32015 filed on Jan. 26, 2009, which claims the benefit ofpriority from U.S. Provisional Application No. 61/023,566, filed on Jan.24, 2008, the entire contents of which are herein incorporated byreference.

TECHNICAL FIELD OF THE INVENTION

This invention relates to the field of interstitial lung diseases andtreatments related thereto.

BACKGROUND OF THE INVENTION

Interstitial Lung Disease (ILD) is a general term that includes avariety of chronic lung disorders. When a person has ILD, the lung isaffected in three ways. First, the lung tissue is damaged in some knownor unknown way. Second, the walls of the air sacs in the lung becomeinflamed. Finally, scarring (or fibrosis) begins in the interstitium (ortissue between the air sacs), and the lung becomes stiff.

Breathlessness during exercise can be one of the first symptoms of thesediseases. A dry cough also may be present. These are common symptomsthat many people ignore. Someone with these symptoms may wait until theyfeel quite ill before going to the doctor. People with different typesof ILD may have the same kind of symptoms but their symptoms may vary inseverity. Their chest X-rays may look alike. Further testing is usuallyrecommended to identify the specific type of ILD a person has. Some ILDshave known causes and some (idiopathic) have unknown causes.

ILD is named after the interstitium because this is the tissue affectedby fibrosis (scarring). ILD is sometimes also known as “interstitialpulmonary fibrosis.” The terms interstitial lung disease, pulmonaryfibrosis and interstitial pulmonary fibrosis are often used to describethe same condition and will be used interchangeably herein.

The course of these diseases is unpredictable. If they progress, thelung tissue thickens and becomes stiff. The work of breathing thenbecomes more difficult and demanding. Some of the diseases improve withmedication if treated when inflammation occurs. Some people may needoxygen therapy as part of their treatment. The diseases may run agradual course or a rapid course. People with ILD may notice variationsin symptoms—from very mild to moderate to very severe. Their conditionmay remain the same for long periods of time or it may change quickly.

While the progress and symptoms of these diseases may vary from personto person, there is one common link between the many forms of ILD. Theyall begin with an inflammation. The inflammation may affect differentparts of the lung, including the following: the walls of the bronchioles(bronchiolitis); the walls and air spaces of the alveoli (alveolitis);the small blood vessels (vasculitis).

Inflammation of these parts of the lung may heal or may lead topermanent scarring of the lung tissue. When scarring of the lung tissuetakes place, the condition is called pulmonary fibrosis.

Fibrosis, or scarring of the lung tissue, results in permanent loss ofthat tissue's ability to transport oxygen. The level of disability thata person experiences depends on the amount of scarring of the tissue.This is because the air sacs, as well as the lung tissue between andsurrounding the air sacs, and the lung capillaries, are destroyed by theformation of scar tissue.

Several causes of pulmonary fibrosis are known, including the following:

Infections: These include viral infections such as cytomegalovirus (aparticular problem for people with compromised immune systems);bacterial infections, including pneumonia; fungal infections such ashistoplasmosis; and parasitic infections.

Occupation and environmental factors: Long-term exposure to a number oftoxins or pollutants can lead to serious lung damage. Workers whoroutinely inhale silica dust (silicosis), asbestos fibers (asbestosis)or hard metal dust are especially at risk of debilitating lung disease.So are people exposed to certain chemical fumes—sulfuric acid, forexample—and ammonia or chlorine gases. But chronic exposure to a widerange of substances, many of them organic, also can damage your lungs.Among these are grain dust, sugar cane, and bird and animal droppings.Other substances, such as moldy hay, can be a problem when they cause ahypersensitivity reaction in the lungs (hypersensitivity pneumonitis).Even bacterial or fungal overgrowth in poorly maintained humidifiers andhot tubs can cause lung damage.

Radiation: A small percentage of people who receive radiation therapyfor lung or breast cancer show signs of lung damage months (or sometimesyears) after the initial treatment. The severity of the damage dependson how much of the lung is exposed to radiation, the total amount ofradiation administered, whether chemotherapy also is used and thepresence of underlying lung disease.

Drugs: Nearly 50 drugs can damage the interstitium of the lungs,especially chemotherapy drugs, medications used to treat heartarrhythmias and other cardiovascular problems, certain psychiatricmedications, and some antibiotics.

Other medical conditions: ILD can occur with other disorders. Often,those conditions don't directly attack the lungs, but instead involvesystemic processes that affect tissue throughout the body. Among theseare connective tissue disorders and hematological diseases, includingsystemic lupus erythematosis, rheumatoid arthritis, dermatomyositis,polymyositis, Sjogren's syndrome and sarcoidosis.

Idiopathic pulmonary fibrosis: Although doctors can determine why somepeople develop ILD, in most cases the cause isn't known. Disorderswithout a known cause are considered a subset of ILD and are groupedtogether under the label idiopathic pulmonary fibrosis or idiopathicILD. Although the idiopathic diseases have certain features in common,each also has unique characteristics.

Usual interstitial pneumonitis is the most prevalent of the idiopathicILDs. Accounting for more than half of all cases, it's so common thatthe terms “usual interstitial pneumonitis” and “idiopathic pulmonaryfibrosis” are often used interchangeably. Because usual interstitialpneumonitis develops in patches, some areas of the lungs are normal,others are inflamed and still others are marked by scar tissue. Thedisease affects twice as many men as women and usually develops betweenthe ages of 40 and 70.

Although the names are nearly identical, pneumonitis is not the same aspneumonia. Pneumonitis is lung inflammation without infection, whereaspneumonia is lung inflammation that results from infection. In addition,pneumonia is generally limited to one or two areas of the lungs, butpneumonitis involves all five lobes—two in the left lung and three inthe right.

Other, less common types of idiopathic pulmonary fibrosis includenonspecific interstitial pneumonitis, bronchiolitis obliterans withorganizing pneumonia (BOOP), respiratory bronchiolitis-associated ILD,desquamative interstitial pneumonitis, lymphocytic interstitialpneumonitis, acute interstitial pneumonitis and bronchopulmonarydysplasia.

Shortness of breath is the main symptom of idiopathic pulmonaryfibrosis. Since this is a symptom of many types of lung disease, makingthe correct diagnosis may be difficult. The shortness of breath mayfirst appear during exercise. The condition then may progress to thepoint where any exertion is impossible.

Other symptoms may include a dry cough (without sputum). When thedisease is severe and prolonged, heart failure with swelling of the legsmay occur.

A very careful patient history is an important tool for diagnosis ofidiopathic pulmonary fibrosis. The history will include environmentaland occupational factors, hobbies, legal and illegal drug use,arthritis, and risk factors for diseases that affect the immune system.A physical examination, chest X-ray, pulmonary function tests, and bloodtests are important.

Bronchioalveolar lavage (BAL), a test which permits removal andexamination of cells from the lower respiratory tract, may be used todiagnose idiopathic pulmonary fibrosis. This test helps identifyinflammation in lung tissue, and also helps exclude infections andmalignancies (cancer) as a cause of a patient's symptoms. The test isdone during bronchoscopy, a special examination of the lung.

A lung biopsy can also be performed, either during bronchoscopy or as asurgical procedure that removes a sample of lung tissue for your doctorto study. This procedure is usually required for diagnosis of idiopathicpulmonary fibrosis.

Other diagnostic tests for idiopathic pulmonary fibrosis include: bloodtests, pulmonary function tests, chest x-ray and CT scan, to name a few.

There are several different treatment regimens for use in ILD and therelated conditions, including the following:

Lung transplantation: This may be an option for younger people withsevere forms of ILD who aren't likely to benefit from other treatmentoptions. In order to be considered for a transplant, you must agree toquit smoking if you smoke, be healthy enough to undergo surgery andpost-transplant treatments, be willing and able to follow the medicalprogram outlined by the rehabilitation and transplant team, and have thepatience and emotional strength and support to undergo the wait for adonor organ. The last is particularly important because donor organs arein short supply. In general, single-lung transplants are more successfulin people with ILD than double-lung transplants are. And although manypeople who receive lung transplants enjoy a good quality of life, thesurvival rate is lower than it is for other types of transplants.Additionally, there is a quality of life issue with respect to theincreased susceptibility to infection, high blood pressure, diabetes andcancer due to the life-long administration of the anti-rejection drugs.

Oxygen therapy: Although oxygen cannot stop lung damage, it can makebreathing and exercise easier, prevent or lessen complications from lowblood oxygen levels, and improve sleep and sense of well-being forafflicted patients. It can also reduce blood pressure on the right sideof the heart. Children with ILD are especially likely to need oxygentherapy.

Cytotoxic drugs: Azathioprine, which is normally used to prevent organrejection after a transplant, and the anti-cancer drug cyclophosphamidemay be used to treat ILD by suppressing inflammation. The drugs areprescribed when corticosteroids fail to improve symptoms or,increasingly, as a first-line treatment in combination withcorticosteroids. Cytotoxic drugs can cause severe side effects,including reduced production of red blood cells, skin cancer andlymphoma.

Antifibrotics: These drugs are used to help reduce the development ofscar tissue. In clinical studies, these drugs have shown promise forslowing the progression of lung damage without suppressing the immunesystem, but real-world results have been disappointing.

Systemic corticosteroid drugs: Although systemic anti-inflammatorydrugs, such as prednisone or methyl prednisolone, are the initialtreatment of choice, they help only about one in five people with ILD.Those most likely to benefit have a non-idiopathic disorder andreversible changes in their lungs. Systemic corticosteroids seldomimprove lung function in people with idiopathic pulmonary fibrosis. Ifbenefits are shown, they are usually temporary in nature. In general,corticosteroid administration lasts for several months until symptomsimprove, at which point the administration is tapered. Upon return ofthe symptoms, further steroid therapy or an immunosuppressive drug suchas azathioprine may be recommended. Taken for long periods of time or inlarge doses, systemic corticosteroids can cause a number of sideeffects, including glaucoma, bone loss, high blood sugar levels leadingto diabetes, poor wound healing and increased susceptibility toinfection. Corticosteroids may be administered to treat the inflammationpresent in some people with IPF. The success of this treatment for manyforms of pulmonary fibrosis is variable and is still being researched.Other drugs are occasionally added when it is clear that thecorticosteroids are not effective in reversing the disease. Some doctorsmay use corticosteroids in combination with other drugs when thediagnosis is first established. Which drug treatment plan is effectiveand how long to use the drugs is the focus of current research.

Pulmonary complications after allogeneic hematopoietic celltransplantation (HCT) remain a major cause of morbidity and mortality.Among the estimated 50,000 to 60,000 hematopoietic cell transplantationsperformed each year (www.ibmtr.org), approximately 30% to 60% of thetransplant recipients will experience a pulmonary complication(Cordonnier C et al., Cancer, 1986; 58:1047-1054; Jules-Elysee K et al.,Am Rev Respir, Dis 1992; 146:485-491. A need exists in the field todevelop a therapeutic alternative to combat the progression of ILD andthe related conditions.

SUMMARY OF THE INVENTION

The present invention provides a novel approach for treating ILD byadministering an oral dosage form of beclomethasone dipropionate (BDP)and exposing the pulmonary circulation to a metabolite of BDP, themetabolite being 17-beclomethasone monopropionate (17-BMP).

In one aspect, the present invention provides a method for delivering acorticosteroid or a metabolite thereof to a subject's pulmonary arteryby administering to the subject an oral dosage of the corticosteroid. Inone embodiment, the corticosteroid is BDP and the metabolite is 17-BMP.Alternatively, the present invention includes any corticosteroidadministration used for the alleviation of inflammatory systems, as wellas its metabolite.

In another aspect, the present invention provides a pharmaceuticalcomposition for treating damage resulting from ILD comprising 17-BMP.

In another aspect, the present invention provides a method forpreventing, ameliorating and/or treating damage resulting from ILD, themethod comprising delivering to a subject's pulmonary artery ametabolite of an orally administered corticosteroid.

In yet another aspect, this invention provides methods which increasethe delivery of medicaments to lung tissue.

The present invention is based on the discovery that topically activecorticosteroids administered orally resulted in a 4-8 fold increase inthe quantity of active drug delivered to the lungs over the amount ofactive drug delivered via an inhalation route. Side effects usuallyattributed to systemic corticosteroids are therefore minimized bydelivery of active drug to the pulmonary artery and by rapid clearanceof such drug from the systemic circulation, while controlling the tissueinflammation within the lung.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts cumulative incidence of non-infectious pulmonarycomplications after treatment randomization. Vertical dashed lineindicates Day 200 after treatment randomization. Prior to Day 200 aftertreatment randomization, no cases of non-infectious pulmonarycomplications occurred among the BDP-treated patients.

FIG. 2 depicts cumulative incidence of pulmonary infections aftertreatment randomization. Vertical dashed line indicates Day 200 aftertreatment randomization. There were no statistically significantdifferences in the risk of pulmonary infections between the twotreatment groups at Day 200 or one year after randomization.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “an effective amount” as used herein refers to a quantity oftopically active corticosteroid which will, upon single or multiple doseoral administration to the patient, be effective in the prophylaxis,amelioration and/or treatment of damage to the structures of the lungcaused by or related to inflammation.

The term “preventing, ameliorating and/or treating” as used hereinrefers to a reduction or elimination of subsequent damage compared withthe damage which would have occurred if the oral corticosteroid were notadministered; and in the case where the oral corticosteroid isadministered after the damage has occurred, a reduction or eliminationof such damage.

The term “damage” as used herein refers to any alteration in normalstructure or function.

By “lining” is meant any biological material which covers a surface orlines a cavity or the like and which performs protective, screeningand/or other functions.

By “topically active” or “locally active”, is meant the compound has itsprincipal pharmacological action through tissue near the site where thedrug is present. In the case of a topically active corticosteroid (TAC),there is limited systemic exposure either by limited absorption, firstpass metabolism by the liver and/or gut, enterohepatic recirculation,protein binding, or rapid elimination from the systemic circulation, andany combination thereof.

By “systemic circulation” it is meant that portion of the circulationwhich is anatomically distal to the pulmonary circulation, or thecirculation resulting from left ventricular outflow into the aorta,arteries, arterioles, capillaries, and venous system, in which asteady-state level of the drug in the circulation has been achieved.

By a “pharmaceutically acceptable carrier or excipient” is meant acarrier or excipient which is compatible with the other ingredients ofthe composition and not injurious to the patient.

The term “effective amount” means that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, system, animal or human that is being sought by aresearcher or clinician.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such amount,results in improved treatment, healing, prevention, or amelioration of adisease or disorder, or a decrease in the rate of advancement of adisease or disorder, and also includes amounts effective to enhancenormal physiological function.

The TACs described in the practice of the present invention can beadministered in buccal and sublingual dosage forms as tablets, capsules(each including timed release and sustained release formulations),pills, powders, granules, elixirs, tinctures, suspensions, syrups andemulsions.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician canreadily determine and prescribe the effective amount of the drugrequired to combat the enteritis and/or mucositis condition.

Oral dosages in the practice of the present invention, when used for theindicated effects, will range between about 0.01 to about 100 mg/kg ofbody weight per day of TAC, and particularly about 0.1 to 10 mg/kg ofbody weight per day. Oral dosage units will generally be administered inthe range of from 0.1 to about 250 mg and more preferably from about 1to about 16 mg. The daily dosage or a 70 kg human will range from 1 mgto 16 mg.

The dosing scheme of the present invention is predicated on the notionthat none of the parent TAC delivered (ie. BDP) can be found in thesystemic circulation, but that 20-40% of the metabolite (ie. 17-BMP)reaches the systemic circulation. It is thus believed that increasingthe parent compound dosing will not result in a burden to the systemiccirculation, but will increase the active metabolite in the pulmonarycirculation.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as “carrier” materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by committing thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

In addition to the TAC, acceptable carriers and/or diluents may beemployed and are familiar to those skilled in the art. Formulations inthe form of pills, capsules, microspheres, granules or tablets maycontain, in addition to one or more TACs, diluents, dispersing andsurface-active agents, binders and lubricants. One skilled in the artmay further formulate the TAC in an appropriate manner, and inaccordance with accepted practices, such as those disclosed inRemington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co.,Easton, Pa., 1990 (incorporated herein by reference). Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate,sodium, benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like. Tablets are formulated, forexample, by preparing a powder mixture, granulating or slugging, addinga lubricant and disintegrant and pressing into tablets. A powder mixtureis prepared by mixing the compound, suitably comminuted, with a diluentor base as described above, and optionally, with a binder such ascarboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone,a solution retardant such as paraffin, a resorption accelerator such asa quate nary salt and/or an absorption agent such as bentonite, kaolinor dicalcium phosphate. The powder mixture can be granulated by wettingwith a binder such as symp, starch paste, acadia mucilage or solutionsof cellulosic or polymeric materials and forcing through a screen. As analternative to granulating, the powder mixture can be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets. The compounds of the present invention can also becombined with free flowing inert carrier and compressed into tabletsdirectly without going through the granulating or slugging steps. Aclear or opaque protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material and a polish coatingof wax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as solution syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds for use according to the present invention can also beadministered in the form of liposome delivery, systems, such as smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

The compounds may also be co-administered with soluble polymers asexcipients or drug carriers. Such polymers can includepolyvinyl-pyrrolidone, pyran copolymer,poly-hydroxypropylmethacryl-amidephenol,poly-hydroxyethyl-aspartamidephenol, or poly-ethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservations and emulsifiers can also be added.

The preferred drugs for use in the composition of the present inventionis BDP and its metabolite, 17-BMP. However, the invention is notrestricted thereto, and relates to any corticosteroid drug which islocally active and delivered as either the parent drug or an activemetabolite to the pulmonary artery for effective treatment ofinflammatory interstitial lung diseases. Representative TACs include,but are not limited to, beclomethasone 17,21-dipropionate, alclometasonedipropionate, budesonide, 228 budesonide, 22R budesonide,beclomethasone-17-monopropionate, clobetasol propionate, diflorasonediacetate, flunisolide, flurandrenolide, fluticasone propionate,halobetasol propionate, halcinonide, mometasone furoate, andtriamcinolone acetonide. Suitable TACs useful in the practice of thisinvention are any that have the following characteristics: rapidfirst-pass metabolism in the intestine and liver, low systemicbioavailability, high topical activity, delivery of active drug to thepulmonary artery and rapid excretion (see, e.g., Thiesen et al.,Alimentary Pharmacology & Therapeutics 10:487-496, 1996) (incorporatedherein by reference).

The preferred drug is BDP, on account of its very high topicalanti-inflammatory activity, and generation within the intestinal tractof a potent metabolite (17-BMP) that is delivered to the pulmonaryartery. BDP can therefore be used effectively in very small doses, inthe compositions of this invention, and will not enter the systemiccirculation to any significant extent. Additionally, the metabolite ofBDP, 17-BMP, may be accessed through oral administration of the parentcompound. Other corticosteroid drugs (such as budesonide) are also ofuse. BDP is a compound that is available from a number of commercialsources, such as Schering-Plough Corporation (Kenilworth, N.J.) in bulkcrystalline form, and has the following structure (i.e., beclomethasone17,21-dipropionate):

Patients receive a therapeutically acceptable amount of a TAC by oraladministration. Suitable capsules or pills generally contain from 0.1 mgto 8 mg TAC, and typically about 1 mg TAC, plus optional fillers, suchas lactose, and may be coated with a variety of materials, such ascellulose acetate phthalate. Such an amount may be readily determined byone skilled in the art by well-known dose-response investigations, andwill generally range from 0.1 mg/day to 8 mg/day, and more typicallyrange from mg/day to 8 mg/day, or higher used in this particularindication.

It will be appreciated that, although specific embodiments of thisinvention have been described herein for purpose of illustration,various modifications may be made without departing from the spirit andscope of the invention.

BDP is a glucocorticoid that when taken orally is metabolized in theintestinal lumen and mucosa to a significantly more potentglucocorticoid metabolite, 17-BMP. Studies in normal human volunteershave demonstrated that none of the parent compound (BDP) can be found inthe systemic circulation, but that 20-40% of the oral drug that reachesthe systemic circulation does so as 17-BMP (Daley-Yates et al). 17-BMPis then rapidly cleared from the circulation. The route by which 17-BMPreaches the circulation is as follows: following formation in theintestine, 17-BMP passes through the portal circulation to the liver,then to the hepatic vein, then to the right atrium and right ventricle,then to the pulmonary artery, the pulmonary vein, then the left atrium,left ventricle, and aorta. Exposure of the pulmonary circulation to thehighly potent immunosuppressive glucocorticoid, 17-BMP, is the basis forthe idea that inflammatory and fibroinflammatory diseases of the lungs,particularly the diseases that involve the interstitium of the lung,might be effectively and safely treated by oral delivery of theglucocorticoid pro-drug BDP. While inhaled BDP is effective in treatingreactive airway diseases that have an inflammatory basis, for example,asthma and chronic obstructive pulmonary disease with chronicbronchitis, inhaled formulations of BDP deliver relatively little 17-BMPto the interstitial space, as much of the inhaled drug reaches thebronchi, smaller airways, and alveoli.

Prednisone therapy is effective in treatment of reactive airway diseaseand some types of ILD, but is limited by systemic toxicity. Topicallyactive, inhaled BDP was developed to allow delivery of glucocorticoid tothe lung so that the systemic toxicity of prednisone could be avoided.

If a person with a pulmonary disorder were given BDP via inhalation, thetotal daily dose of BDP would be a maximum of 400 .micro.grams (0.4 mg).While there is metabolism of BDP to 17-BMP in the lungs, the maximumdaily amount of 17-BMP that reaches the lungs would be limited to 0.4mg. In contrast, if a daily dose of 8 mg. oral BDP were given, and if20-40% of that dose was delivered to the pulmonary artery as 17-BMP, thetotal daily dose of 17-BMP delivered to the lungs would be 1.6 to 3.2mg, a 4- to 8-fold increase in the amount of drug delivered to the lungsover the inhalation route.

Two multicenter, randomized, placebo-controlled, double-blind trialshave been conducted to examine whether oral beclomethasone dipropionate(BDP) is an effective therapy for treatment of gastrointestinalgraft-versus-host disease (GVHD) (McDonald G B et al., Gastroenterology,1996; 115:28-35; Hockenbery D M et al., Blood, 2007; 109:4557-4563). Theresults of these studies indicate that oral BDP is effective fortreating gastrointestinal GVHD, allows rapid taper and less use ofsystemic corticosteroid therapy, and results in a 45% reduction inmortality risk at one year post-randomization. In addition to thesebenefits, the most recent trial revealed that BDP treatment was alsoassociated with fewer cytomegalovirus reactivations (28% versus 39%),fungal infections, (7% versus 14%), and multiple bacteremic episodes(none versus 9%) (Hockenbery D M et al., Blood, 2007; 109:4557-4563).

Of interest to the pulmonary community was the observation that duringthe 80-day study period, 12/67 (18%) patients on the placebo arm haddeveloped noninfectious pulmonary infiltrative disorders, compared to0/62 patients in the BDP treatment arm (17). Based upon this initialobservation, it was believed that oral BDP may be effective inpreserving lung function and preventing the development of earlynoninfectious pulmonary complications after allogeneic HCT. To test thishypothesis, there was a retrospective review of medical records and aprospective collection of pulmonary function test (PFT) results from allpatients who participated in these two randomized trials.

These results represent the first report in the literature of randomizedtrial data demonstrating a treatment strategy that may be not onlyprotective of lung function after HCT, but useful in the prevention ofthe almost uniformly fatal noninfectious pulmonary complications thatoccur in the early post-HCT period. There was a statisticallysignificant preservation of pulmonary diffusing capacity and fewerepisodes of non-infectious pulmonary complications in patientsrandomized to receive oral BDP, compared to placebo. Although theprimary objective in each of the two randomized, placebo-controlledtrials of oral BDP was not to assess pulmonary outcomes, these findingsare consistent with the mortality results of the trials suggesting morefavorable outcome in the group randomized to BDP. These trials assessedthe ability of this topically active glucocorticoid to control the signsand symptoms of gastrointestinal GVHD while minimizing systemicprednisone exposure. In both trials, the frequency of GVHD treatmentfailure was significantly reduced at the end of the treatment period andafter follow-up among patients randomized to BDP, compared to placebo.These results are also consistent with what is known about thepathophysiology of idiopathic lung injury in the aftermath of allogeneicHCT and the pharmacology of oral BDP and its potent metabolite, 17-BMP.

The reported incidence of IPS in the first 120 days after allogeneic HCTis 3 to 15%, with a lower incidence reported in association with the useof reduced intensity conditioning regimens. Respiratory failure isgenerally common and usually rapid in onset, with mortality uniformlyhigh, ranging from GO % to greater than 95% for patients requiringmechanical ventilation. Although a few clinical risk factors have beenconsistently identified in previous studies, including conditioning withtotal body irradiation, acute GVHD, and older recipient age,accumulating evidence from murine models of lung injury after allogeneicHCT strongly suggest that inflammation plays a significant role in thepathogenesis of IPS. Some of these murine studies have established acausal role for TNF-α in the development of IPS, where administration ofa TNF-α binding protein (rhTNFR:Fc) reduces the progression of lunginjury during the four to six week period after HCT. Other studies havealso suggested that lipopolysaccharide (LPS), which often gains accessto systemic circulation early in the post-transplantation period bytranslocating across gut mucosa damaged by conditioning regimens andacute GVHD, may result in a significant inflammatory cytokine milieu inthe lung that results in lung injury (Cooke K R et al., J Clin Invest,1998; 102:1882-1891). Collectively, these data provide strong evidencethat overwhelming inflammation within the lungs likely plays asignificant role in the pathogenesis of early noninfectious pulmonarycomplications after HCT. These studies indicate that a sequence ofevents involving chemokine-driven recruitment of inflammatory andimmune-effector cells to the lung, release of oxidants andproinflammatory cytokines, and, in the case of allogeneictransplantation, a second wave of injury mediated by alloreactive Tlymphocytes, may lead to the development of IPS.

The formulations of oral BDP used in the randomized trials describedhere included a gastric-release pill for distribution of BDP to thestomach and upper small intestine, and an enteric-coated pill fordistribution to the distal small intestine and colon. Presence of 17-BMPin the blood from the right heart, as demonstrated by our data, suggeststhat 17-BMP, a product of gastrointestinal mucosal hydrolysis of BDP,was likely absorbed in the gastrointestinal tract and entered the rightheart via portal venous circulation. In the HCT situation, we speculatethat steady-state delivery of 17-BMP to the pulmonary circulation andultimately the interstitial space prior to the onset of clinicallydetectable disease was responsible for reducing pulmonary inflammation,reflected by the preservation of pulmonary diffusing capacity and by theabsence of noninfectious pulmonary infiltrates within the first 200 daysafter randomization.

Consideration of oral BDP as a preemptive agent for these noninfectiouspulmonary complications may have several advantages. Although BDP itselfis a relatively weak immunosuppressive glucocorticoid, its activemetabolite 17-BMP, is a highly potent glucocorticoid. In a human skinvasoconstriction model, where the degree of blanching (vasoconstriction)was interpreted as indicating anti-inflammatory activity, 17-BMP was3.6-times more potent than triamcinolone-16,17-acetonide, the activeingredient in Azmacort inhalation aerosol (Kos Pharmaceuticals) and450-times more potent than dexamethasone (Harris D M et al., J SteroidBiochem, 1975; 6:711-716).

17-BMP is also much more potent in terms of glucocorticoid receptor-αactivity. In competition binding assays, where the affinity value fordexamethasone was arbitrarily set at 100 and affinity values of theother corticosteroids were calculated based on their reduction ofspecific binding of radiolabeled dexamethasone, 17-BMP's bindingaffinity was approximately 13-times as potent as dexamethasone (relativebinding affinities were BDP: 43, 17-BMP: 1345) (Wurthwein G et al.,Biopharm Drug Dispos, 1990; 11:381-394). Finally, the relativebioavailability of BDP and its metabolites is much lower in comparisonto more commonly used corticosteroids. In a bioavailability study oforal BDP, where BDP was given orally and intravenously to 12 healthysubjects, no BDP was detectable in the plasma following oraladministration. However, the total oral bioavailability of the activemetabolite 17-BMP was 21-41%(unpublished data). Systemic exposure to17-BMP is limited by its protein binding and clearance, such that oralBDP 2 mg would give systemic exposure equivalent to a dosing schedule oforal prednisone of 2.5 mg or less than 1 mg of intravenousdexamethasone.

EXAMPLES Example I Preservation of Pulmonary Diffusing Capacity withOral Beclomethasone Dipropionate

Patients with biopsy-proven acute gastrointestinal GVHD received aninduction course of prednisone (1 mg/kg/day for 10 days) plus eitheroral BDP pills (8 mg/day in four divided doses, half as agastric-release formulation and half as an enteric-coated formulation)or placebo. Patients whose symptoms were controlled at study day tencontinued on study drug while the prednisone dose was rapidly tapered.Patients whose symptoms required additional prednisone were consideredtreatment failures. Study drug was discontinued on the day of treatmentfailure. The duration of treatment with study drug was 30 days with a10-day follow-up period in the first trial and 50 days with a 30-dayfollow-up period in the second trial.

Pulmonary Function Testing

Pulmonary function assessments included forced vital capacity (FVC),one-second forced expiratory volume (FEV1), total lung capacity (TLC),and carbon monoxide diffusion capacity (DL_(CO)), which was adjusted forhemoglobin level at the time PFTs were obtained. All PFT values wereexpressed as a percent of the predicted value calculated according topublished equations (Crapo R O et al., Am Rev Respir Dis, 1981;123:659-664; Crapo R O et al., Am Rev Respir Dis, 1981; 123:185-189).Pre-transplantation and Day 80 PFTs were obtained, regardless of thepresence or absence of symptoms. After discharge, patients wereencouraged to return at one year after transplantation, at which timeanother PFT was obtained. For purposes of the current study, PFTsperformed between days 60 and 100 were considered as valid for the Day80 PFT and tests performed between days 265 and 465 as valid for theone-year PFT. Change in lung function was assessed by comparing PFTparameters performed prior to start of conditioning to those obtainedpost-transplantation at Day 80 and one year. Analysis of change in lungfunction was done on an intent-to-treat basis, by randomizationassignment to oral BDP or placebo, with maintenance of the study blind.

Sixty patients had been randomized to oral BDP and the same number toplacebo. Serial PFTs at day 80 were available from 44 and 50 patients onplacebo and BDP, respectively. Significantly fewer patients randomizedto BDP (55%) had deterioration of diffusing capacity by transplant day80, compared to placebo (79%), p=0.02. No such differences were noted inother PFT parameters (see Table 1). In the analysis of change in PFTsfrom baseline to Day 80, eight patients who did not meet the minimumfive-day criterion of treatment with study drug prior to their Day 80PFT were not included (five in placebo group, three in BDP group). Themedian time to randomization was 33.5 days after HCT (range, 19-105) forthe Phase 2 study and 31 days (range, 16-89) for the Phase 3 study.Several patients were missing baseline, Day 80, or one-year PFT asindicated by the total number of patients contributing to theappropriate analyses summarized Tables 1 and 2. Overall, the majority ofthe patients had normal pulmonary function prior to transplantation,defined as a percent of the normal predicted value≧80% [FVC 94/114(82%); FEV1 88/114 (77%); TLC 105/113 (93%); DL_(CO) 84/114 (74%)].

TABLE 1 Proportion of patients whose PFTs decreased from pre- HCTbaseline to transplant day 80 and magnitude of changes, by randomizationassignment (chi square test). PFT parameter Placebo BDP p-value FEV₁ N(%)* 21/44 (48) 25/50 (50) 0.83 Mean change (range) −1.38 (−25, +19)−0.05 (−22, +34) 0.48 FVC N (%)* 24/44 (55) 25/50 (50) 0.66 Mean change(range) −1.85 (−20, +16) +0.34 (−30, +35) 0.26 TLC N (%)* 25/42 (60)29/50 (58) 0.88 Mean change (range) −1.67 (−20, +23) +1.41 (−25, +57)0.23 DLCO N (%)* 33/42 (79%) 27/49 (55) 0.02 Mean change (range) −7.95(−40, +23) +0.57 (−74, +115) 0.08 FVC = forced vital capacity, FEV₁ =one second forced expiratory volume, TLC = total lung capacity, DLCO =dffusion capacity of carbon monoxide *N represents proportion ofpatients who experienced a decrease in that parameter

TABLE 2 Characteristics of BDP and placebo treated patientsCharacteristic Placebo (N = 60) BDP (N = 60) Median age (range) 47(12-66) 40 (7-67) Recipient:donor sex M:M 17 24 M:F 11 12 F:F 12 9 F:M20 15 Disease CML 13 15 AML 16 19 MDS 17 3 ALL 8 8 NHL 2 8 Other 4 7Donor type Unrelated 24 20 Related matched 31 32 Related mismatched 3 7Conditioning regimen TBI-based myeloablative 28 31 Non-TBI-basedmyeloablative 28 18 Nonmyeloablative 4 11 Randomized study Phase II 2931 Phase III 31 29 Pulmonary function pretransplant * FVC (n = 58, 56)95.1 93.7 FEV₁ (n = 58, 56) 89.9 90.4 TLC (n = 57, 56) 98.6 95.7 DLCO (n= 58, 56) 90.9 83.6 Pulmonary function at Day 80 * FVC (n = 49, 56) 93.093.8 FEV₁ (n = 49, 56) 89.2 90.3 TLC (n = 48, 55) 96.7 96.9 DLCO (n =47, 54) 81.2 86.0 pulmonary function at one year * FVC (n = 29, 33) 94.089.4 FEV₁ (n = 29, 33) 88.5 85.9 TLC (n = 28, 33) 98.9 95.7 DLCO (n =27, 33) 74.4 78.1 M = male; F = female; CML = chronic myeloid leukemia;AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; ALL =acutelymphocytic leukemia; NHL = non-Hodgkins lymphoma; TBI = total bodyirradiation, FVC = forced vital capacity, FEV₁ = one second forcedexpiratory volume, TLC = total lung capacity, DLCO = dffusion capacityof carbon monoxide * Numbers represent the mean of the percent ofpredicted normal values

Changes in pulmonary function from pre-transplantation to Day 80 aftertransplantation are summarized in Table 1. The proportion of BDP- andplacebo-treated patients who experienced a decrease (of any magnitude)of their pulmonary function from pretransplantation to Day 80 aftertransplantation was similar for FVC, FEV1, and TLC, with nostatistically significant differences. However, there was astatistically significant difference in the proportion of patients whoexperienced a decrease of the DL_(CO). Among placebo treated patients,33 of 42 (79%) patients experienced a decrease of the DL_(CO) frompre-transplantation to Day 80 after transplantation, compared to 27 of49 (55%) BDP-treated patients (p=0.02). The mean decrease amongplacebo-treated patients was 7.95% (range −40% to +23%), while the meanchange from baseline to Day 80 was actually increased 0.57% forBDP-treated patients (range −74% to +115%) (p=0.08).

Additional analysis of PFTs obtained at one year after transplantationdid not reveal any statistically significant associations of treatmentwith loss of pulmonary function. However, the decrease from baseline toone year in DL_(CO) was larger in the placebo group compared to the BDPgroup (placebo: mean decrease of 15.27% among 27 patients with data;BDP: mean decrease of 7.67% among 32 patients with data; p=0.11). In theBDP group, four noninfectious events occurred after Day 200 (FIG. 1;COP/BOOP on Day 207, IPS on Day 212, bronchiolitis obliterans syndromeon Day 244, DAH on Day 269). The COP/BOOP and DAH cases occurred after amyeloablative conditioning regimen, the IPS and bronchiolitis obliteranssyndrome cases occurred after a reduced-intensity conditioning regimen.In the placebo group, a case of bronchiolitis obliterans syndrome in apatient conditioned with a myeloablative regimen was diagnosed on Day311 after randomization. When all data from the first year afterrandomization were considered, the risk of developing a noninfectiouscomplication remained lower among BDP-treated patients, but this did notreach statistical significance (HR=0.70, 95% confidence interval [CI]0.19-2.57, p=0.58). The overall risk of developing a pulmonary infectionby one year was lower for the BDP group, although this was notstatistically significant (HR=0.67 (0.27-1.66, p=0.38)).

Among 60 placebo-treated patients, four noninfectious complicationsoccurred within the first 200 days after randomization (FIG. 1). Thesecases were COP/BOOP (Day 39) and IPS (Day 69, 148, 168). All of thesecases occurred after a myeloablative conditioning regimen. Among 60BDP-treated patients, there were no cases of noninfectious pulmonarycomplications during the first 200 days after randomization (FIG. 1).When considered as a time-to-event endpoint, the risk of developing anoninfectious complication within the first 200 days after randomizationwas reduced among BDP-treated patients, (hazard ratio [HR]=0, p=0.04;p=0.06 with the exact log-rank test).

These data suggest that oral BDP may have a protective effect on earlydecline in pulmonary diffusing capacity, which commonly occurs by Day 80after transplant because of interstitial lung injury. We hypothesizethat preservation of diffusing capacity was due to delivery of thepotent immunosuppressive metabolite 17-BMP to the lungs via GI mucosa,portal vein, and pulmonary artery.

Example II Categorization of Pulmonary Disease after Hematopoietic CellTransplantation

While blinded to randomization assignment, investigators reviewed allpatients' pulmonary radiologic records accumulated from the time ofrandomization to one year after transplantation. The medical records ofall patients with abnormal pulmonary radiological findings were reviewedto determine whether the pulmonary disease was a clinically significantnoninfectious or infectious syndrome. Clinically significantnoninfectious pulmonary syndromes included idiopathic pneumonia syndrome(IPS), defined as widespread alveolar injury in the absence of activelower respiratory tract infection after HCT (Freudenberger T D et al.,Blood, 2003; 102:3822-3828, diffuse alveolar hemorrhage (DAH), definedas IPS with bronchioalveolar lavage showing progressively bloodierreturn, or biopsy-proven cryptogenic organizing pneumonia (COP)otherwise known as bronchiolitis obliterans organizing pneumonia (BOOP).Clinically significant pulmonary infection required microbiologicdocumentation of an infectious agent in the respiratory tract viabronchoscopy or resolution of pulmonary abnormalities after empiricalantibiotic therapy with no addition of immunosuppressive agents.

The causes of pulmonary infections are summarized in Table 3. Among 60placebo-treated patients, 11 cases of pulmonary infection occurred afterrandomization during the first year, five (45%) of which occurred withinthe first 200 days after randomization (FIG. 2). Among 60 BDP-treatedpatients, 8 cases of pulmonary infection occurred during the first yearafter randomization, 6 (75%) of which occurred during the first 200 daysafter randomization (FIG. 2). When considered as a time-to-eventendpoint, the risk of developing a pulmonary infection was notstatistically significantly different between BDP and placebo (HR=1.21(0.37-3.96, p=0.75)).

TABLE 3 Causes of pulmonary infection according to treatment groupPlacebo Oral BDP Day post- Day post- Cause of infection randomizationCause of infection randomization Fungal, nonspecific 41 Legionella spp.27 Aspergillus fumigatus 59 Polymicrobial bacteria 31 Unknown cause 125Pseudomonas aeruginosa 48 Aspergillus spp, 142 Candida glabrata 83Unknown cause 143 Unknown cause 85 Pneumocystis jiroveci 209 Unknowncause 104 Aspergillus spp, 216 Parainfluenza and 210 Aspergillus spp.Unknown cause 219 Klebsiella pneumoniae 293 Aspergillus terreus 270Candida spp. 275 Streptococcus hominis 373

Example III Measurement Of 17-Beclomethasone Monopropionate (17-BMP) inBlood from the Right Atrium

Four FHCRC patients enrolled in the Phase 3 randomized study hadparticipated in a sub-analysis of BDP pharmacokinetics. At study Day 50,blood was drawn from the right atrium via an indwelling Hickman catheterat frequent intervals after a morning dose of oral BDP 2 mg (1 mg eachin gastric-release and enteric-coated tablets). Blood samples werecollected over EDTA, plasma was collected after centrifugation at 4° C.,and aliquots were frozen at −20° C. until analysis for BDP and 17-BMPusing high-pressure liquid chromatography and mass spectroscopy (MDSPharma Services, Montreal, Canada). Pharmacokinetic parameters werecalculated using WinNonlin v.2.1 (Pharsight Corp, Palo Alto Calif.).Plasma concentration-time data were plotted and non-compartmentalparameters were calculated using the linear trapezoidal rule. Estimatesfor half-lives were obtained using regression analysis by specifying anappropriate range of time points for the most linear portions of the logconcentration-linear time data.

Peak concentrations of 17-BMP in right atrial blood were achieved at amedian of 1.5 hours after oral dosing of BDP 2 mg on the morning ofstudy Day 50. The median C_(max), was 1738 pg/mL (range 632-3701).Median steady state exposure to 17-BMP was 5347 pg·hr/mL (range3273-5201) as estimated by AUC_(0-4 hr). The median half-life of 17-BMPwas 6.3 hours (range 3.1-6.8). No BDP was detected in right atrialblood.

1. A method of treating an interstitial lung disease comprising oraldelivery of an effective amount of a topical active corticosteroidsufficient to expose a metabolite thereof to the pulmonary circulationof a subject.
 2. The method of claim 1, wherein the topical activecorticosteroid is beclomethasone dipropionate.
 3. The method of claim 1,wherein the metabolite is 17-beclomethasone monopropionate.
 4. Themethod of claim 1, wherein the effective amount of the topical activecorticosteroid is at least 8 mg/day.
 5. The method of claim 1, whereinthe interstitial lung disease includes at least one member of the groupconsisting of idiopathic pulmonary fibrosis, nonspecific interstitialpneumonitis, bronchiolitis obliterans with organizing pneumonia,respiratory bronchiolitis-associated interstitial lung disease,desquamative interstitial pneumonitis, lymphocytic interstitialpneumonitis, acute interstitial pneumonitis and bronchopulmonarydysplasia.
 6. A method of delivering a corticosteroid or metabolitethereof to a subject's pulmonary artery for treatment of an interstitiallung disease by administering to the subject an effective amount of anoral dosage of the corticosteroid or metabolite.
 7. The method of claim6, wherein the topical active corticosteroid is beclomethasonedipropionate.
 8. The method of claim 6, wherein the metabolite is17-beclomethasone monopropionate.
 9. The method of claim 6, wherein theeffective amount of the topical active corticosteroid is at least 8mg/day.
 10. The method of claim 6, wherein the interstitial lung diseaseincludes at least one member of the group consisting of idiopathicpulmonary fibrosis, nonspecific interstitial pneumonitis, bronchiolitisobliterans with organizing pneumonia, respiratorybronchiolitis-associated interstitial lung disease, desquamativeinterstitial pneumonitis, lymphocytic interstitial pneumonitis, acuteinterstitial pneumonitis and bronchopulmonary dysplasia.
 11. A methodfor preventing, ameliorating and/or treating damage resulting from aninterstitial lung disease, the method comprising delivering to asubject's pulmonary artery a metabolite of an orally administeredcorticosteroid in a dose that is at least 5 fold greater than thecorticosteroid delivered via inhalation.
 12. The method of claim 11,wherein the topical active corticosteroid is beclomethasonedipropionate.
 13. The method of claim 11, wherein the metabolite is17-beclomethasone monopropionate.
 14. The method of claim 11, whereinthe effective amount of the topical active corticosteroid is at least 8mg/day.
 15. The method of claim 11, wherein the interstitial lungdisease includes at least one member of the group consisting ofidiopathic pulmonary fibrosis, nonspecific interstitial pneumonitis,bronchiolitis obliterans with organizing pneumonia, respiratorybronchiolitis-associated interstitial lung disease, desquamativeinterstitial pneumonitis, lymphocytic interstitial pneumonitis, acuteinterstitial pneumonitis and bronchopulmonary dysplasia.